Endometriosis is defined in The Merck Manual, 17th edition, Merck & Co., Inc., Whitehouse Station, N.J., USA, chapter 239, as “a nonmalignant disorder in which functioning endometrial tissue is present outside the uterine cavity.” It is sometimes referred to as endometriosis externa or adenomyosis externa. Endometriotic tissues contain estrogen and progestogen receptors that enable them to grow and differentiate in response to the changes in hormonal levels during the menstrual cycle. Endometriosis is usually confined to the peritoneal or serosal surfaces of abdominal organs, commonly the ovaries, posterior broad ligament, posterior cul-de-sac, and uterosacral ligaments (sometimes forming uterosacral nodules). Less common sites include the serosal surfaces of the small and large bowel, ureters, bladder, vagina, surgical scars, pleura, and pericardium. Clinical manifestations of endometriosis are pelvic pain, pelvic mass, alteration of menses, and infertility, while lesions on the bowel or bladder may cause pain during defecation or urination, abdominal bloating, and rectal bleeding with menses (most endometriatic implants can bleed during menstruation). Endometriotic implants on the ovary or adnexal structures can form an endometrioma (a cystic mass localized to an ovary) or adnexal adhesions. Endometriosis is reportedly found in 10-15% of women between the ages of 25 and 44 who are actively menstruating, and in 25-50% of infertile women.
Internal endometriosis includes adenomyosis or adenomyoma. Adenomyosis, also referred to as endometriosis interna, is the invasion of endometrial tissue into the muscular tissue (myometrium) of the uterus. If the lesion is generalized the lesion is called adenomyosis and when it is localized to a smaller area of the uterus it is called adenomyoma. It causes symptoms in only a small number of patients, usually late in the reproductive years. Menorrhagia and intermenstrual bleeding are the most common complains, followed by pain, especially menstrual pain, and bladder and rectal pressure. Oral contraceptive steroids and GnRH agonists or antagonists are not regarded as effective, and oral contraceptives may aggravate the symptoms. Only surgery (myomectomy or hysterectomy) is regarded as curative.
Treatments for endometriosis include medical suppression of ovarian function to arrest the growth and activity of endometrial implants, conservative surgical resection of as much endometriotic tissue as possible, a combination of these two treatments, and total hysterectomy, usually with removal of the ovaries and Fallopian tubes. Medical therapy involves estrogen suppression, such as by administration of continuous oral contraception with estrogen/progestogen combination products (with the usual side effects including abdominal swelling, breast tenderness, breakthrough bleeding, and deep vein thrombosis), gonadotropin-releasing hormone (GnRH) agonists or antagonists such as intranasal nafarelin and subcutaneous or depot leuprolide (with the usual side effects including hot flushes, emotional lability, vaginal dryness, and bone demineralization, but the treatment is usually limited to less than six months because of the risk of bone loss), androgens such as oral danazol (with the usual side effects including masculinization effects such as weight gain, acne, and hirsutism, and other side effects including emotional lability, atrophic vaginitis, liver dysfunction, and adverse effects on lipids), and progestogens such as oral and/or intramuscular medroxyprogesterone (with the usual side effects including breakthrough bleeding, weight gain, emotional lability, depression, and atrophic vaginitis).
For example, Lamb, U.S. Pat. No. 4,038,389, discloses an aqueous parenteral formulation of medroxyprogesterone (INN—referred to as medroxyprogesterone acetate) containing a suspension of 200-600 g·L−1 of micronized medroxyprogesterone in a mixture of water, sodium sulfate, a quaternary ammonium wetting agent, and glycerol, propylene glycol, polyethylene glycol, or polypropylene glycol, optionally containing a hydrophilic colloid.
Labrie, U.S. Pat. No. 5,362,720, discloses a method for the treatment of breast and endometrial cancer, osteoporosis, and endometriosis by administration of a low dose of a progestogen or other steroid derivative having androgenic activity and low masculinizing activity, for example, medroxyprogesterone. Various routes of administration are suggested, with subcutaneous depot preferred, intending to achieve a serum concentration of <50 nmol·L−1, preferably between 1 nmol·L−1 and 10, 15 or 25 nmol·L−1 depending on the patient response.
Bologna et al., U.S. Pat. No. 5,543,150, discloses a method of progesterone therapy for the prevention of endometrial cancer using relatively low serum progesterone concentrations such as 1-6 μg·L−1, achieved by vaginal delivery using crosslinked polycarbophil as a vehicle.
International PCT application No. WO 00/15766, U.S. Pat. No. 6,287,602, and US Patent Application Publication No. 2002/0012703, each describe pharmaceutical formulations for treating a cellular proliferative disease (for example, a cancer, including endometrial cancer) comprising a Golgi apparatus disturbing agent, a biocompatible carrier, and a solvent. A Golgi apparatus disturbing agent is brefeldin A and a biocompatible carrier is chitin or chitosan. The formulation can include another active agent, including medroxyprogesterone, and the preferred route of administration is said to be intratumoral or intralesional (defined as an area sufficiently close to a tumor that the active agent exhibits the desired pharmacological activity with respect to the tumor itself).
International PCT publication No. WO 02/28387 and U.S. Patent Application Publication No. 2002/0061303, each disclose a formulation containing a Golgi apparatus disturbing agent (such as the agents described in WO 00/15766) present in an angiogenesis-inhibiting but non-cytotoxic amount, a solvent, and a pharmaceutically acceptable carrier. These are for treating a patient in need of anti-angiogenic therapy.
International PCT publication No. WO 00/21511, discloses the use of subcutaneous progestogens for the treatment of endometriosis. Suitable progestogens are said to include medroxyprogesterone, progesterone, norethisterone, desogestrel, and levonorgestrel.
Ragavan et al., U.S. Pat. No. 6,416,778, describes formulations for regional delivery of drugs, including steroids such as progestins, estrogens, antiestrogens, and antiprogestins, especially micronized danazol in a micro- or nanoparticulate formulation. These formulations can be used for the treatment of endometriosis, endometrial bacterial infections, cancer, and endocrine conditions.
None of these treatments are as effective as desired. Accordingly, there is a need to develop effective medical treatments for endometriosis, including endometriosis externa, endometrioma, adenomyosis, adenomyomas, endometriotic or adenomyotic nodules of the uterosacral ligaments and endometriotic nodules elsewhere such as scar endometriosis. Therefore, among the objects herein, it is an object to provide more effects methods for treatment of endometriosis and compositions therefor.